MDMA (3,4-methylenedioxymethamphetamine) and related phenethylamines (i.e. methamphetamine, MDA, etc.) are popular drugs of abuse which have been found to be serotonin (5-HT) neurotoxins. Single or repeated administration of MDMA to rodents as well as nonhuman primates results in long term damage to brain 5-HT axon terminals. The mechanism by which MDMA and related compounds produce their neurotoxic effect is unknown. The objective of the proposed studies is to demonstrate that acute administration of MDMA activates dopamine (DA) neurons in the substantia nigra resulting in the prolonged and excessive release of DA in brain regions innervated by nigrostriatal pathways. It is hypothesized that excessive synaptic concentrations of DA are taken up into 5-HT axon terminals where DA can be autoxidized resulting in the production of highly reactive quinones which can damage axon terminals. The ability of MDMA to increase the extracellular concentrations of DA, 5-HT and their metabolites will by studied using in vivo microdialysis. The acute effect of MDMA on carrier and impulse-mediated DA and 5-HT release will be determined in the nigrostriatal cell bodies (substantia nigra) and terminal regions (striatum). On the basis of preliminary studies, it is hypothesized that MDMA increases dopaminergic neurotransmission by 2 mechanisms: (1) direct release of DA from axon terminals via a carrier-mediated exchange and (2) releasing 5-HT in the substantia nigra which stimulates 5-HT-2/1C receptors resulting in impulse (vesicle) mediated release of DA in the striatum. It is hypothesized that repeated administration of MDMA will produce a sensitization of DA pathways and that sensitized animals will be more susceptible to the 5-HT neurotoxic effect of MDMA. In addition, MDMA is expected to cross-sensitize with amphetamine. Finally, it is hypothesized that MDMA will increase the formation of cysteine-DA adducts as a result of the interaction between quinones, formed from DA autoxidation, and sulfydryl groups located within the axon terminal. The acute effects of MDMA on the release of DA and 5-HT will be directly related to the long-term neurotoxic effects of this compound by measuring the extent of brain 5-HT depletion as well as the loss of 5-HT uptake sites in the same animal 7 days following the microdialysis studies. Collectively, it is anticipated that these studies will establish the neurochemical events which produce 5-HT neurotoxicity following the administration of MDMA. Cross-sensitization between amphetamine and MDMA resulting in enhanced neurotoxicity is suggestive that chronic stimulant abusers may be more susceptible to MDMA-induced 5-HT depletion, even with infrequent patterns of abuse. Finally, the mechanism(s) by which MDMA produces it neurotoxicity may serve as a model to predict whether other abused drugs are potential 5-HT neurotoxins.